The present invention is directed to methods of treating neurodegenerative conditions by increasing extracellular concentrations of adenosine.
The etiology of major neurodegenerative diseases is not understood. Such diseases, which include Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease) and Alzheimer's Disease, have proved difficult to treat; few if any therapies have proved effective in slowing or arresting the degenerative process.
Parkinson's Disease is a prevalent neurodegenerative disease which generally affects older people. As noted above, its specific etiology is not well understood; however, a Parkinson-like syndrome can result from exposure to certain chemical substances. Two such substances, methamphetamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), have been used as models for studying Parkinson's Disease.
Parkinson's Disease is characterized by lesions in the brain, particularly affecting the striatum and results in dopamine depletion, particularly in the striatum (nuclei of the basal ganglia, especially substantia nigra, putamen and caudate nucleus). Attempts to alleviate the dopamine depletion in individuals affected with Parkinson's Disease led to the use of L-dopa, a precursor to dopamine which is better able to cross the blood-brain barrier, as a therapeutic agent to alleviate the symptoms of Parkinson's Disease. In order to better target the global effects of L-dopa, it is often given with carbidopa, a peripheral decarboxylase inhibitor which decreases the metabolism of L-dopa in the peripheral tissues.
The systemic administration of either methamphetamine or MPTP to experimental animals has been found to produce degenerative changes in nigrostriatal dopaminergic neurons or their axon terminals Both methamphetamine and MPTP result in decreases in striatal dopamine (DA) and in decreased tyrosine hydroxylase (TH) activity, as well as histochemical indications of nerve terminal degeneration within the neostriatum. It has been postulated that some of those neurodegenerative effects may be associated with overactivity of excitatory amino acid (EAA) neurotransmission. Treatment with noncompetitive blockers of one of the EAA receptors, the N-methyl-D-aspartate (NMDA) receptor has been shown to partially antagonize NMDA-mediated decrements in DA content and TH activity produced by administration of methamphetamine or MPTP. It was postulated that those findings implicated EAA's in neurodegenerative conditions such as Parkinson's Disease. (See, Sonsalla, P. K., et al. "Role for Excitatory Amino Acids in Methamphetamine-Induced Nigrostrial Dopaminergic Toxicity", Science 243: 398-400 (1989)).
Due to their mimicry of effects of Parkinson's Disease, treatment of animals with methamphetamine or MPTP has been used to generate models for Parkinson's Disease. These animal models have been used to evaluate the efficacy of various therapies against Parkinsons's Disease
Administration of MPTP to animals provides a useful Parkinsonian model. The end result of MPTP administration is the destruction of the striatum in the brain, an area in the neocortex limbic system in the subcortical area in the center of the brain, an area compromised in Parkinson's Disease. The neurotransmitter dopamine is concentrated in the striatum Parkinson's Disease is characterized by lesions in that area of the brain and by depleted dopamine levels. In some species (primates) the striatal degeneration has been reported to be accompanied by behavioral symptoms that mimic Parkinson's symptoms in humans.
Methamphetamine also compromises the striatum, but is somewhat less selective than MPTP and may induce strial degeneration by a different mechanism than MPTP.
Adenosine, 9-.beta.-D-ribofuranosyladenine (the nucleoside of the purine adenine), belongs to the class of biochemicals termed purine nucleosides and is a key biochemical cell regulatory molecule, as described by Fox and Kelly in the Annual Reviews of Biochemistry, Vol 47, p. 635, 1978.
Adenosine interacts with a wide variety of cell types and is responsible for a myriad of biological effects. Adenosine serves a major role in brain as an inhibitory neuromodulator (see Snyder, S. H., Ann. Rev. Neural Sci. 8: 103-124 1985, Marangos, et al., NeuroSci and Biobehav Rev. 9:421-430 (1985), Dunwiddie, Int. Rev. Neurobiol., 27:63-130 (1985)). This action is mediated by ectocellular receptors (Londos et al., Regulatory Functions of Adenosine, pp. 17-32 (Berne et al., ed.) (1983)). Among the documented actions of adenosine on nervous tissue are the inhibition of neural firing (Phillis et al., Europ. J. Pharmacol., 30:125-129 (1975)) and of calcium dependent neurotransmitter release (Dunwiddie, 1985). Behaviorally, adenosine and its metabolically stable analogs have profound anticonvulsant and sedative effects (Dunwiddie et al., J. Pharmacol. and Exptl. Therapeut., 220:70-76 (1982); Radulovacki et al., J. Pharmacol. Exptl. Thera., 228:268-274 (1981)) that are effectively reversed by specific adenosine receptor antagonists. In fact, adenosine has been proposed to serve as a natural anticonvulsant, and agents that alter its extracellular levels are modulators of seizure activity (Dragunow et al., Epilepsia 26:480-487 (1985); Lee et al., Brain Res., 21:1650-164 (1984)). In addition, adenosine is a potent vasodilator, an inhibitor of immune cell function, an inhibitor of granulocyte oxygen free radical production, an anti-arrhythmic, and an inhibitory neuromodulator Considering its broad spectrum of biological activity, considerable effort has been aimed at establishing practical therapeutic uses for adenosine and its analogs.
Since adenosine is thought to act at the level of the cell plasma membrane by binding to receptors anchored in the membrane, past work has included attempts to increase extra-cellular concentrations of adenosine by administering it into the blood stream. Unfortunately, because adenosine is toxic at concentrations that have to be administered to a patient to maintain an efficacious extracellular therapeutic concentrations, the administration of adenosine alone is of limited therapeutic use. Further, adenosine receptors are subject to negative feedback control following exposure to adenosine, including down-regulation of the receptors.
Other ways of achieving the effect of a high local extracellular concentration of adenosine exist and have also been studied. They include: a) interference with the uptake of adenosine with reagents that specifically block adenosine transport, as described by Paterson et al., in the Annals of the New York Academy of Sciences, Vol. 255, p. 402 (1975); and Deckert et al., in Life Sciences, Vol. 42, page 1331 to 1345; b) prevention of the degradation of adenosine, as described by Carson and Seegmiller in The Journal of Clinical Investigation, Vol. 57, p. 274 (1976); and c) the use of analogs of adenosine selectively to bind to adenosine receptors.
Compounds which selectively increase extracellular adenosine would also be useful in the prophylactic protection of cells in the hippocampus implicated in memory. The hippocampus has more adenosine and glutamate receptors than any other area of the brain. Accordingly, as described below, it is most sensitive to stroke or any condition of low blood flow to the brain. Some recent studies suggest that Alzheimer's disease may result from chronic subclinical cerebral ischemia. Accordingly, compounds which selectively increase extracellular adenosine levels may be used for the treatment and/or prevention of both overt stroke and Alzheimer's disease.
It is now established that relatively short periods of brain ischemia (on the order of 2 to 8 minutes) set into motion a series of events that lead to an eventual death of selected neuronal populations in brain. This process is called delayed excitotoxicity and it is caused by the ischemia-induced enhancement of the release of the excitatory amino acid neurotransmitters, including glutamate and aspartate. Within a period of hours to days post-stroke, some neurons in brain are overstimulated by EAA's to the point of metabolic exhaustion and death. Because over-released glutamate appears to be the major factor involved in post-stroke cell damage, the blockade of glutamate receptors in brain could be beneficial in stroke therapy. In animals, glutamate receptor blockers have been shown to be effective in alleviating or preventing stroke-associated neural damage. These receptor blockers have, however, been shown to lack specificity and produce many undesirable side effects. Church, et al., "Excitatory Amino Acid Transmission," pp. 115-118 (Alan R. Liss, Inc. 1987).
Adenosine has been shown to be a potent inhibitor of glutamate release in brain. The CA-I region of brain is selectively sensitive to post-stroke destruction. In studies where observations were made at one, three and six days poststroke, the CA-I area in the hippocampus was shown to be progressively destroyed over time. However, where cyclohexyladenosine ("CHA"), a global adenosine agonist, was given shortly after the stroke, the CA-1 area was markedly protected. (Daval et al., Brain Res., 491:212-226 (1989) and Marangos, Med. Hypothesis 32:45-49 (1990)). That beneficial effect was also seen in the survival rate of the animals. Because of its global effect, however, CHA has non-specific side effects. For example it undersirably will lower blood pressure, slow the heart and markedly raise blood glucose.
Hyperglycemia has been reported to be associated with a poor prognosis for stroke (Helgason, Stroke 19(8) :1049-1053 (1988)). In addition, mild hypoglycemia induced by insulin treatment has been shown to improve survival and morbidity from experimentally induced infarct (LeMay et al., Stroke 19(11):1411-1419 (1988)). AICA riboside and the prodrugs of the present invention could protect against ischemic injury to the central nervous system (CNS) by their ability to lower blood glucose.
Another area of medical importance is the treatment of neurological diseases or conditions arising from elevated levels of homocysteine (e.g., vitamin B12 deficiencies). The AICA riboside prodrugs may be used for such purposes as well.
During seizures, certain neural cells fire abnormally. ATP catabolism is greatly accelerated in the abnormally firing cells leading to increased adenosine production. Adenosine has marked anticonvulsant effects and, thus, has been termed the brain's natural anticonvulsant. It appears to play a major role in the brain as an inhibitory neuromodulator; this action of adenosine is apparently mediated by certain ectocellular receptors. Adenosine has both post-synaptic and pre-synaptic effects. Among the documented effects of adenosine on nervous tissue are the inhibition of neural firing and of calcium dependent neurotransmitter release. Behaviorally, adenosine and its metabolically stable analogs have profound anticonvulsant and sedative effects.
As stated above, adenosine has been proposed to serve as a natural anticonvulsant with agents that alter its extra-cellular concentration acting as a modulator of seizure activity Besides acting as a neuromodulator, adenosine is a potent vasodilator, an inhibitor of granulocyte oxygen free radical production, an antiarrhythmic. In fact, because of the many actions of adenosine, it has been called a "retaliatory molecule" released to protect cells against certain pathologic assaults.
Unfortunately, adenosine is toxic at concentrations that have to be administered systemically to a patient to maintain an efficacious extracellular therapeutic concentration at the target organ, and the administration of adenosine alone so far has been of limited therapeutic use. Likewise, since most cells in the body carry receptors for adenosine, the use of techniques that increase adenosine concentrations generally throughout the body can cause unwanted, dramatic changes in normal cellular physiology.